1. Field of the Invention
This invention describes new treatments that should provide for relief from several nervous system disorders with reduced side effects, and it involves the administration of a norepinephrine reuptake inhibitor, preferably a selective norepinephrine reuptake inhibitor such as the drug reboxetine, in combination with a neuroleptic agent (typical or atypical antipsychotic agents). In particular, the combination is to be used to treat schizophrenia.
2. Technology Description
The introduction of tricyclic antidepressants in the early 1960s has provided a major advance in the treatment of neuropsychiatric disorders. Reactive and endogenous depressions, diagnoses formerly carrying grave prognostic implications, have become, with the introduction of the tricyclics, manageable disorders with a much smaller toll on the patient and the society as a whole.
The early tricyclic compounds were reuptake inhibitors of all the catecholamines released in the synaptic cleft, thus resulting in prolongation and enhancement of the dopamine (DA), noradrenaline (NA) and serotonin (5-hydroxytryptamine=5-HT) action. Lack of selectivity also causes undesired side effects particularly on the acetylcholine (especially the muscarinic component), and histamine mediated neurotransmission.
Because of these unwanted pharmacodynamic activities, cognitive impairment, sedation, urinary and gastrointestinal tract disturbances, and increased intraocular pressure were limiting factors in the clinical use of these compounds and often required discontinuation of treatment. Of utmost concern were also the cardiac toxic effects and the proconvulsant activity of this group of drugs.
More recently, selective reuptake inhibitors for serotonin (SSRI) have been introduced with definite advantages in regard to fewer side effects without loss of efficacy. Fluoxetine is an example of such an inhibitor that has had a great amount of commercial success.
Another class of compounds that has been proposed for use in the treatment of depression is selective norepinephrine reuptake inhibitors. Lower-than-normal levels of norepinephrine are associated with a variety of symptoms including lack of energy, motivation, and interest in life. Thus, a normal level of norepinephrine is essential to maintaining drive and capacity for reward. These neurotransmitters travel from the terminal of a neuron across a small gap (i.e., the synaptic cleft) and bind to receptor molecules on the surface of a second neuron. This binding elicits intracellular changes that initiate or activate a response or change in the postsynaptic neuron. Inactivation occurs primarily by transport (i.e., reuptake) of the neurotransmitter back into the presynaptic neuron. Abnormality in noradrenergic transmission results in various types of depression, mental, behavioral, and neurological disorders attributed to a variety of symptoms including a lack of energy, motivation, and interest in life. See generally, R. J. Baldessarini, “Drugs and the Treatment of Psychiatric Disorders: Depression and Mania” in Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, NY, N.Y., pp. 432-439 (1996).
Examples of norepinephrine reuptake inhibitors (both selective and not selective) include, but are not limited to the following: tandamine (CAS 42408-80-0; U.S. Pat. Nos. 3,904,617; 4,118,394), pirandamine (CAS 42408-79-7; U.S. Pat. No. 3,995,052), ciclazindol (CAS 37751-39-6; U.S. Pat. No. 3,891,644; No. 3,957,819; No. 3,976,645), fluparoxan (U.S. Pat. No. 4,880,801), lortalamine (CAS 70384-91-7; U.S. Pat. No. 4,201,783), talsupram (CAS 21489-20-3), talopram (CAS 7182-51-6), prindamine, nomifensine (U.S. Pat. No. 3,577,424), viloxazine (U.S. Pat. No. 3,712,890), tomoxetine (U.S. Pat. No. 4,314,081), duloxetine (U.S. Pat. No. 5,023,269), venlafaxine (U.S. Pat. No. 4,535,186), milnacipran (U.S. Pat. No.4,478,836) and reboxetine (U.S. Pat. No. 4,229,449).
The term schizophrenia was first used in 1911 by Eugen Bleuler, a Swiss psychiatrist, to diagnose patients whose thought processes and emotional responses seemed to be disconnected. The term schizophrenia literally means split mind and many people still believe incorrectly that the condition causes a split personality (actually an uncommon problem involving dissociation). Schizophrenia is now used to describe a cluster of symptoms that typically includes delusions, hallucinations, disordered thinking, and emotional unresponsiveness. No clear-cut definition of schizophrenia exists even at this time and no single cause has been found to explain all aspects of this devastating syndrome. Most likely, the symptoms are triggered by a number of disease processes coupled with genetic factors and environmental stresses.
Chemical treatment for those suffering from schizophrenia include the use of neuroleptic agents (sometimes referred to as antipsychotic agents) of either the typical or atypical type.
Typical neuroleptic agents are those that block receptors of the neurotransmitter dopamine. These medications are also referred to as neuroleptic drugs, because they can cause a number of neurologic side effects. The first drug of this type used for treating schizophrenia was chlorpromazine (Thorazine; U.S. Pat. No. 2,645,640). Many other antipsychotic drugs are now available, the most popular being haloperidol (Haldol; U.S. Pat. No. 3,438,991). Others include perphenazine (Trilafon; U.S. Pat. No. 2,766,235), thioridazine (Mellaril; dosage of 30-800 mg/day), mesoridazine (Serentil; U.S. Pat. No. 3,084,161), trifluoperazine (Stelazine; U.S. Pat. No. 2,921,069), and fluphenazine (Prolixin; U.S. Pat. No. 3058979). For the very severe active phase of schizophrenia, injections of an antipsychotic drug are often given every four to eight hours until the patient is calm. If possible, however, physicians prefer administering a drug orally. These drugs may be high- or low-potency. Generally, higher doses are used to treat acute episodes (e.g., 5 to 10 mg of haloperidol) and lower doses are given during periods of remission (e.g., 2 to 5 mg). However, new studies suggest starting haloperidol treatment with daily doses in the 4 to 5 mg range for two to three weeks. The beneficial impact of these drugs is greatest on psychotic symptoms, particularly hallucinations and delusions in the early and midterm stages of the disorder. In patients who are being treated for the first time, improvement in psychotic symptoms may be evident within one or two days of treatment, although the full benefit of the drug usually evolves over about six to eight weeks. Thought disturbances are reduced more gradually. Some estimates of poor responses to these drugs are as high as 40%. Antipsychotic drugs are also not very successful in reducing negative symptoms, although people often show less withdrawal and apathy because of the reduction in psychotic episodes. The most disturbing common side effects of high-dose or high-potency therapy of typical antipsychotic drugs are those known as extrapyramidal symptoms, which effect the nerves and muscles controlling movement and coordination. The most serious long term extrapyramidal effect of antipsychotic therapy is tardive dyskinesia, a condition associated with repetitive and involuntary movements, or tics, most often in the mouth, lips, and tongue and also in the legs, arms and trunk. Symptoms range from mild to severe, and sometimes interfere with eating and walking. They may not appear until the antipsychotic drugs have been taken for months or even years. A condition known as acute dystonia can occur shortly after taking antipsychotic drugs. This side effect causes abnormal muscle spasms, particularly sustained contortions of the neck, jaw, trunk, and eye muscles. High potency drugs (e.g., haloperidol, fluphenazine) cause less drowsiness and very low blood pressure but induce more extrapyramidal side effects. Low-potency drugs (e.g., chlorpromazine, thioridazine) are more sedating and side effects are not as acute. Nearly every neuroleptic drug can cause extrapyramidal side effects, however, which occur in up to 70% of patients taking these medications. After the drug is withdrawn, symptoms can sometimes persist for weeks or months. Women face a higher risk for these symptoms, and they increase with length of therapy and age. These medications can have adverse side effects on many organs and systems in the body. Sleepiness and lethargy commonly occur in the beginning of therapy, but usually decrease over time. Other side effects include dry mouth, eye problems, allergic reactions, temporary weight gain, and menstrual irregularities in women. A much more serious but rare side effect is the neuroleptic malignant syndrome, in which dangerously high body temperatures occur. Without prompt and expert treatment, this side effect can be fatal in 20% of those who develop it. Sometimes the effects of the drugs mimic schizophrenic symptoms, such as agitation, slow speech, and retarded movement, and so the physician may be tempted to increase the dosage.
Drugs known as atypical drugs (also referred to in this document as atypical neuroleptic or atypical antipsychotic agents) are rapidly changing treatment for schizophrenia, and many experts are now urging that they be used as the primary treatment for certain patients instead of the antipsychotics. Atypical drugs appear to be more effective than the neuroleptics, even in reducing negative symptoms and preventing relapse. They are rarely associated with the extrapyramidal side effects, particularly tardive dyskinesia. The most successful atypical drugs are able to simultaneously affect dopamine receptors and other neurotransmitters responsible for psychotic symptoms. Clozapine (U.S. Pat. No. 3,539,573), olanzapine (U.S. Pat. No. 5,229,382), and risperidone (U.S. Pat. No. 4,804,663) are currently the standard atypical drugs, but new medication that may be even more effective are becoming available. Clozapine (Clozaril) is the best known of these drugs. Clozapine was found to benefit up to half of patients with schizophrenia who did not respond to other types of treatments, and there is now substantial evidence of its superiority over typical drugs. It is particularly useful in younger people, although toxic side effects are common. Positive effects may not be evident for up to nine months. Clozapine has improved negative symptoms in short-term trials; longer ones are needed to see if the benefit is sustained. It may also reduce aggressive behavior and suicidal impulses. Although the drug does not appear to cause tardive dyskinesia, it does have other side effects including nasal congestion, drooling, low blood pressure, headache, sleeplessness, and significant weight gain. Serious side effects include seizures and, in up to 1% of cases, agranulocytosis—a potentially life-threatening decrease in the patient's white blood cells. When agranulocytosis develops, it usually does so within three months of treatment, peaking in the third month; if it hasn't appeared within six months, it most likely will not develop. Older women are at higher risk for this side effect. Agranulocytosis can be reversed if treatment with clozapine is stopped at once. It is important that people taking clozapine have their serum glucose level count monitored frequently, especially those with diabetes or a family history of diabetes. Although clozapine is more expensive than haloperidol, this extra expense may be offset by its greater efficacy, which results in fewer hospitalizations. Risperidone. Risperidone (Risperdal) is a dopamine receptor blocker that has shown benefit and even superiority in comparison to antipsychotics. It is now used by about 20% of schizophrenia patients. Like clozapine, risperidone may have a beneficial effect on negative symptoms. Risperidone may also improve verbal working memory, a common problem in schizophrenics. It has few extrapyramidal effects, although they can occur at higher doses. Common side effects include sleepiness, weight gain, and dizziness. Olanzapine. Olanzapine (Zyprexa) may be more effective in blocking the neurotransmitters serotonin and dopamine than is clozapine and have a much lower risk for seizures and agranulocytosis. Studies indicate it is at least as effective for acute symptoms and possibly more effective for negative ones than the typical neuroleptic drugs and that it has a very low risk for extrapyramidal symptoms. The drug may also be beneficial for patients who do not respond to neuroleptic drugs. A new study suggests that olanzapine also may be more effective than risperidone, particularly in its effect on negative symptoms, but more research is needed to confirm result. Like risperidone, olanzapine can cause sleepiness, weight gain, and dizziness. Other Atypical Drugs. Ziprasidone (U.S. Pat. No. 4,831,031) and quetiapine (Seroquel; U.S. Pat. No. 4,879,288), which has recently been approved by the FDA, are other promising new drugs. Ziprasidone affects serotonin as well as dopamine may also improve negative symptoms with limited extrapyramidal side effects. Sertindole (Serlect; U.S. Pat. No. 4,710,500) is another drug well into development. Although promising, reports of increased risk for sudden cardiac death are of some concern. Aripiprazole (U.S. Pat. No. 5,006,528) is another atypical drug in development.
Still other drugs for the treatment of schizophrenia include, but are not limited to the following typical and atypical neuroleptic agents: blonanserin (U.S. Pat. No. 5,021,421), iloperidone (EP 402644), perospirone (U.S. Pat. No. 4,745,117), raclopride (U.S. Pat. No. 4,789,683), sonepiprazole (U.S. Pat. No. 5,877,317), zotepine (U.S. Pat. No. 3,704,245), DU-127090, ORG-5222 (GB 1567862), SM-13496, amisulpride (U.S. Pat. No. 4,401,822), CP-361428, Lu 35-138, balaperidone (WO 94/00458), S-18327 (EP 811622), WAY-135452 (also known as DAB-452), eplivanserin (EP 373998), E-5842 (WO96/4287), SR-31742 (EP 461986), NE-100 (EP 641766), osanetant (EP512901, EP 673928), SR-141716 (EP 658546), SR-48692 (EP 477049), BSF-201640 (WO99/09015), BSF-190555 (WO95/07274), LAX-101a, sarizotan (EP 707007), CX-691 (U.S. Pat. Nos. 5,783,587, 5,891,876) and SB-271046 (WO98/27081).
Despite the above advances in the art, it would be desirable to develop a pharmaceutical composition that would have both the therapeutic benefits of the neuroleptic agents (typical or atypical) with a reduced side effects.